Virions are endogenous smart nanoparticles (NPs) that are evolutionarily optimized to achieve efficient reproduction in host cells. The viral surface plays a crucial role in establishing successful infection since it facilitates the binding of virus particles to the host cell and the subsequent initiation of an uptake program that results in the delivery of the viral genetic content to the intracellular virus replication machinery. Many of these interactions are facilitated by specific virus-encoded proteins, such as gp120 (HIV-1 envelope glycoprotein) in the case of productive (or cis) HIV-1 infection of CD4+ T cells and macrophages. There is, however, a growing body of evidence that some infection mechanisms also depend critically on the composition of the viral lipidome. In particular, host derived glycosphingolipids (GSLs) incorporated into the virion play a central role for HIV-1 uptake and transmission by mature DCs, a DC-mediated HIV-1 trans-infection pathway. The GSL that mediates the glycoprotein-independent interactions between HIV-1 and mature DCs was identified as monosialodihexosylganglioside (GM3),8,11 and the type 1 interferon inducible Siglec1,
CD169, has been identified as the corresponding receptor that recognizes GM3 present in the membrane of HIV-1 particles. Furthermore, virus particles captured by CD169 in a GM3-dependent manner are sequestered in non-lysosomal compartments, and upon initiation of DC-T cell contacts transferred to the DC-T cell synaptic junction, termed “virological synpase”. Since the cytoplasmic tail of CD169 lack any known endocytic motifs, many details of the mechanisms underlying CD169-mediated HIV-1 uptake and subsequent trafficking to DC-T cell virological synapses remain currently unclear. The latter is—at least in part—due to experimental complications associated with a systematic investigation of the role of individual host-encoded viral surface functionalities in trans-infection. One particular challenge is that the compositional complexity of both cellular and viral surfaces gives rise to a multitude of potential interactions that can be both physical and chemical in nature and which are difficult to decouple in conventional virus models. A second complication is that mechanistic information about the cellular machinery orchestrating the virus trafficking is best obtained by single virus trafficking. This approach requires, however, bright labels that facilitate an optical tracking with high temporal resolution, ideally without limitation in maximum observation time.
Different virus model systems have been developed for delivery purposes as well as for structural or mechanistic studies. Successful realizations include virus like particles (VLPs), virus-based nanoparticles, liposomes, and hybrid systems in which biomolecules are combined with inorganic nanoparticles to reproduce viral functionality. None of the systems implemented so far, however, fulfill all the specific requirements with regard to size, transducing capability, surface composition, and engineerability to characterize the mechanistic role of GM3 in the membrane of the HIV-1 virion. For instance, HIV-1 Gag VLPs, which are common tools for characterizing the role of non-virus encoded host cell surface functionalities, are immature virion cores wrapped in a lipid bilayer derived upon budding from a virus-producer cell and can contain host-derived membrane glycoproteins in addition to a broad range of different (glyco)lipids. These additional groups can compete or interfere with the biological functionality of GM3. Clearly, there is a desire for better designs of engineered virion mimics.